DESCRIPTION (adapted from the application) The molecular mechanisms ultimately responsible for maintaining potassium homeostasis reside in the tubular epithelial cells of the kidney. It is becoming increasingly clear that the predominant ionic pathways necessary for luminal potassium recycling and secretion, as well as, for the movement of potassium across basolateral membranes in the nephron take the form of highly regulated potassium-selective protein multimers that belong to the extensive inward rectifier K+ channel family. A radical departure from the antiquated classical model of a potassium channel as a passive ion-conducting pore, inward rectifier K+ channels are complex molecular machines whose constituent subunits undergo cooperative conformational changes, exhibit modulatory intersubunit interactions, and interact distinctively with numerous regulatory factors during the process of conducting potassium ions through a pore lined by multiple ion binding sites. A multitude of intracellular factors and processes have been shown to participate in the remarkably intricate regulation of renal inward rectifier K+ channels. These include not only intracellular concentrations of magnesium, polyamines, protons, ATP, ADP, PIP2, and arachidonic acid, but also the processes of protein phosphorylation by cAMP-dependent protein kinase, protein kinase C, and calcium-calmodulin-dependent kinase II. It is the purpose of this research program to investigate a novel regulatory mechanism that appears to distinguish certain inward rectifier K+ channel subunits belonging to the Kir1 (ROMK) and Kir4 subfamilies that are strongly expressed in the kidney. Through this mechanism, extracellular potassium acts as a modulatory factor to control the "gain" of renal inward rectifier K+ channel currents. We hypothesize that the mechanism, designated "K+ regulation," will have significant physiological implications not only for epithelial cells in the nephron, but also for excitable cells such as muscle cells and neurons.